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Human iPSC-based Modeling of Late-Onset Disease using Progerin-induced Aging

ABSTRACT: Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) sets their identity back to an embryonic age. This presents a fundamental hurdle for modeling late-onset disorders using iPSC-derived cells. We therefore developed a strategy to induce age-like features in multiple iPSC-derived lineages and tested its impact on modeling Parkinson’s disease (PD). We first describe markers that predict fibroblast donor age and observed the loss of these age-related markers following iPSC induction and re-differentiation into fibroblasts. Remarkably, age-related markers were readily induced in iPSC-derived fibroblasts or neurons following exposure to progerin including dopamine neuron-specific phenotypes such as neuromelanin accumulation. Induced aging in PD-iPSC-derived dopamine neurons revealed disease phenotypes requiring both aging and genetic susceptibility such as frank dendrite degeneration, progressive loss of tyrosine-hydroxylase expression and enlarged mitochondria or Lewy body-precursor inclusions. Our study presents a strategy for inducing age-related cellular properties and enables the modeling of late-onset disease features.

ORGANISM(S): Homo sapiens

PROVIDER: GSE52431 | GEO | 2014/01/23

SECONDARY ACCESSION(S): PRJNA228920

REPOSITORIES: GEO

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Human iPSC-based Modeling of Late-Onset Disease using Progerin-induced Aging

Project description:Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) sets their identity back to an embryonic age. This presents a fundamental hurdle for modeling late-onset disorders using iPSC-derived cells. We therefore developed a strategy to induce age-like features in multiple iPSC-derived lineages and tested its impact on modeling Parkinson’s disease (PD). We first describe markers that predict fibroblast donor age and observed the loss of these age-related markers following iPSC induction and re-differentiation into fibroblasts. Remarkably, age-related markers were readily induced in iPSC-derived fibroblasts or neurons following exposure to progerin including dopamine neuron-specific phenotypes such as neuromelanin accumulation. Induced aging in PD-iPSC-derived dopamine neurons revealed disease phenotypes requiring both aging and genetic susceptibility such as frank dendrite degeneration, progressive loss of tyrosine-hydroxylase expression and enlarged mitochondria or Lewy body-precursor inclusions. Our study presents a strategy for inducing age-related cellular properties and enables the modeling of late-onset disease features. Induced pluripotent stem cell-derived midbrain dopamine neurons from a young and old donor overexpressing either GFP or Progerin.

2014-01-23 | E-GEOD-52431 | biostudies-arrayexpress

Single cell sequencing of iPSC-dopamine neurons reconstructs disease progression and identifies HDAC4 as a regulator of Parkinson cell phenotypes

Project description:Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson’s disease (PD) but neuronal cultures are confounded by cellular heterogeneity. By applying high-resolution single cell transcriptomic analyses to Parkinson’s iPSC-derived dopamine neurons carrying the GBA-N370S risk variant, we exploited intra-culture cellular heterogeneity to identify a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Analysis of genes differentially-expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with compounds known to modulate HDAC4 activity upregulated genes early in the DE axis, and corrected Parkinson’s-related cellular phenotypes. Our study demonstrates how single cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets.

2018-10-17 | E-MTAB-7303 | biostudies-arrayexpress

Proteomic analysis of GBA iPSC-dopamine neurons

Project description:Heterozygous mutations in the glucocerebrosidase gene (GBA) are the strongest common genetic risk factors for Parkinson’s disease (PD) present in around 5-10% of PD patients, resulting in lower age of onset and exacerbating disease progression, including an increased risk of dementia. However, the exact mechanisms leading from dysfunction of the enzyme glucocerebrosidase (GCase) encoded by GBA to PD pathogenesis and neurodegeneration remain unclear. Applying a novel multi-part enrichment workflow we have developed, we have isolated and quantified peptides with phosphorylation, cysteine-modification or N-linked glycosylation simultaneously. We applied this methodology to iPSC-derived dopaminergic neurons from GBA-N370S PD patients and healthy age-matched controls, identifying large numbers of dysregulated native and modified proteins.

2023-03-04 | PXD026691 | Pride

A stably self-renewing adult blood-derived induced neural stem cell exhibiting patternability and epigenetic rejuvenation

Project description:Recent reports suggest that induced neurons (iNs), but not induced pluripotent stem cell (iPSC)-derived neurons largely preserve age-associated traits. Here we report on the extent of preserved epigenetic and transcriptional aging signatures in directly converted induced neural stem cells (iNSCs). Employing restricted and integration-free expression of SOX2 and c-MYC we generate a fully functional, bona fide NSC population from adult blood cells that remains highly responsive to regional patterning cues. Upon conversion, low passage iNSCs display a profound loss of age-related DNA methylation signatures, which further erode across extended passaging, thereby approximating the DNA methylation age of isogenic iPSC-derived neural precursors. This epigenetic rejuvenation is accompanied by a lack of age-associated transcriptional signatures and absence of cellular aging hallmarks. We find iNSCs to be competent for modeling pathological protein aggregation and for neurotransplantation, depicting blood-to-NSC conversion as a rapid alternative route for both disease modeling and neuroregeneration.

2018-11-01 | GSE117720 | GEO

Homo sapiens

Project description:Human iPSC-based Modeling of Late-Onset Disease using Progerin-induced Aging

| PRJNA228920 | ENA

Investigating the role of p16 and cellular senescence in Alzheimer’s disease pathogenesis

Project description:Advancing age is the greatest risk factor for Alzheimer’s Disease (AD), as most AD patients are age 65 and older. However, the mechanistic contribution of aging to AD is unclear. Cellular senescence, one of the major hallmarks of aging, is recently implicated as an aggravator of AD pathogenesis. The critical senescence regulator p16 is increased in neurons of AD patients and mouse models. Eliminating p16-expressing senescent cells attenuates AD pathologies in AD mouse models. However, what p16 does in post-mitotic neurons and how p16 contributes to AD pathogenesis remains unknown. As clinical trials continually fail to improve cognitive decline in AD patients, it is increasingly important to develop a better human cell-based model system to advance our understanding of the impact of aging in AD pathogenesis. Induced pluripotent stem cell (iPSC) technology has revolutionized human disease modeling, enabling differentiation to relevant brain cell types for the study of AD pathogenesis in a human cell-based culture environment. AD iPSC-derived neurons exhibit higher levels of Amyloid beta secretion and tau phosphorylation compared to non-demented control iPSC-derived neurons. Nevertheless, iPSC-derived neurons are “fetal-like” and fail to recapitulate the aging process in AD pathogenesis. Thus, we have developed a robust human iPSC-based neuron model to investigate the contribution of p16 expression to cellular senescence and AD pathogenesis. We found that inducible p16 expression leads to senescence phenotypes in AD as well as non-demented control iPSC-derived neurons. The impact of p16 and induced senescence in neurons on the cellular pathologies of AD is investigated. Our study provides a novel approach to investigate aging-associated cellular changes that potentially influence AD patient-derived differentiated neurons to age and become more permissive to AD pathogenesis in culture.

2023-12-31 | GSE252132 | GEO

Age-induced midbrain-striatum assembloids model early phenotypes of Parkinson’s disease [RNA-Seq]

Project description:Parkinson's disease (PD), one of the most common aging-associated neurodegenerative disorders, is characterised by nigrostriatal pathway dysfunction, caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain and the dopamine depletion in the striatum. State of the art, human in vitro models are enabling the study of the dopaminergic neurons' loss, but not the dysregulation of the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics which potentially contribute to the development of PD. Therefore, it is conceivable that research conducted using these models overlooked numerous processes that contribute to disease's phenotypes. Here we present a nigrostriatal pathway model based on midbrain-striatum assembloids with inducible aging. We show that these assembloids are capable of developing characteristics of the nigrostriatal connectivity, with dopamine release from the midbrain to striatum and synapses formation between midbrain and striatal neurons. Moreover, progerin-overexpressing assembloids acquire aging traits that lead to early phenotypes of PD. This new model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of PD.

2023-10-28 | GSE236458 | GEO

Untargeted Mass Spectrometry Metabolomic Profiles of iPSC-derived Dopaminergic Neurons from Clinically Discordant Brothers with Identical PRKN Deletions

Project description:We have previously reported on two brothers, PM and SM, who carry identical compound heterozygous PRKN mutations but present with very different clinical Parkinson’s disease (PD) phenotypes, with PM, but not SM having been diagnosed with early onset disease. The occurrence of juvenile cases demonstrates that PD is not necessarily an age-associated disease, indeed evidence is accumulating that there is a developmental component to PD pathogenesis. We hypothesize that additional genetic modifiers, potentially including genetic loci relevant to mesencephalic dopamine neuron development may play a role. We differentiated human-induced pluripotent stem cells (hiPSCs) derived from SM and PM into mitotically active mesencephalic neural precursor cells and early postmitotic dopaminergic neurons and performed whole exome sequencing, transcriptomic- and metabolomic analyses. No significant differences in canonical markers of differentiation were observed between SM and PM. Yet our transcriptomic analysis revealed a significant down regulation of three neurodevelopmentally relevant cell adhesion molecules, CNTN6, CNTN4 and CHL1 in PM- compared to SM cultures on days 11 and 25 of differentiation. In addition, several HLA genes, known to play a role in neurodevelopment, independent of their well-established function in immunity, were differentially regulated in PM and SM developing dopamine neurons. EN2, a transcription factor crucial for mesencephalic dopamine neuron development, was also differentially regulated. We further observed differences in cellular processes relevant to dopamine homeostasis. Lastly, our whole exome sequencing, transcriptomics and metabolomics data of SM and PM neurons revealed differences in GSH homeostasis, the dysregulation of which has been associated with PD.

2021-10-13 | ST001957 | MetabolomicsWorkbench

Quantitative proteomic profiling of the rat substantia nigra places glial fibrillary acidic protein at the hub of proteins dysregulated during aging: Implications for idiopathic Parkinson’s disease

Project description:There is a strong correlation between aging and onset of idiopathic Parkinson’s disease, but little is known about whether cellular changes occur during normal aging that may explain this association. Here, proteomic and bioinformatic analysis was conducted on the substantia nigra of rats at four stages of life to identify and quantify protein changes throughout aging. This analysis revealed that proteins associated with cell adhesion, protein aggregation and oxidative-reduction are dysregulated as early as middle age in rats. Glial fibrillary acidic protein (GFAP) was identified as a network hub connecting the greatest number of proteins altered during aging. Furthermore, the isoform of GFAP expressed in the substantia nigra varied throughout life. However, the expression levels of the rate-limiting enzyme for dopamine production, tyrosine hydroxylase (TH), was maintained even in the oldest animals, despite a reduction in the number of dopamine neurons in the SNc as aging progressed. This age-related increase in TH expression per neuron would likely to increase the vulnerability of neurons, since increased dopamine production would be an additional source of oxidative stress. This, in turn, would place a high demand on support systems from local astrocytes, which themselves show protein changes that could affect their functionality. Taken together, this study highlights key processes that are altered with age in the rat substantia nigra, each of which converge upon GFAP. These findings offer insight into the relationship between aging and increased challenges to neuronal viability, and indicate an important role for glial cells in the aging process.

2020-03-20 | PXD017018 | Pride

Age-induced midbrain-striatum assembloid models early phenotypes of Parkinson’s disease [scRNA-Seq]

Project description:Parkinson’s disease, one of the most common aging-associated neurodegenerative disorders, is characterised by nigrostriatal pathway dysfunction, caused by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain and the dopamine depletion in the striatum. State of the art, human in vitro models are enabling the study of the dopaminergic neurons’ loss, but not the dysregulation of the dopaminergic network in the nigrostriatal pathway. Additionally, these models do not incorporate aging characteristics necessary for the development of PD. Therefore, it is conceivable that research conducted using these models overlooked numerous processes that contribute to disease’s phenotypes. Here we present a method for the generation of a midbrain-striatum assembloid model with inducible aging. Aging is induced by expression of progerin. We show that these assembloids are capable of developing characteristics of the nigrostriatal connectivity, with dopamine release from the midbrain to striatum and synapses formation between midbrain and striatal neurons. Moreover, progerin-overexpressing assembloids acquire aging phenotypes that lead to early phenotypes of Parkinson’s disease. This new model shall help to reveal the contribution of aging as well as nigrostriatal connectivity to the onset and progression of PD.

2023-10-28 | GSE241631 | GEO

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